U.S. application Ser. No. 151,210, filed May 19, 1980 in the names of N. F. Borrelli, A. A. Luderer, and J. N. Panzarino, now U.S. Pat. No. 4,323,056, discloses a tumor treatment modality which results in a reduction of tumor mass and may lead to complete eradication of a tumor. The inventive method comprises localized magnetically-coupled, radio frequency (RF)-induced hyperthermia mediated by a material which is non-toxic to and, preferably, inert to or compatible with animal tissue and has incorporated therewithin iron-containing crystals of such size, amount, composition, and magnetic properties to impart a coercive force of at least 200 oersteds to the material, and wherein the frequency of the magnetic field is sufficiently low that essentially only magnetic hysteresis heating of the mediating material can occur.
The mediating or suscepting material is preferably a glass, glass-ceramic, or sintered ceramic with base compositions in the borate, phosphate, or silicate field and having incorporated therewithin iron-containing crystals of magnetite and/or a ferrite selected from the group of lithium, cobalt, nickel, manganese, and barium ferrite. Most preferably, the frequency of the RF magnetic field will not exceed about 10 kilohertz.
That patent discussed previous attempts to treat carcinomata through localized hyperthermia. Thus, early workers had implanted powdered magnetic materials, identified by those workers to be magnetic Fe.sub.2 O.sub.3, into tissue and those particles became heated when coupled to a magnetic field through their dielectric and hysteresis losses. Those studies employed RF magnetic fields having frequencies of about 0.12-2 megahertz. Although those experiments demonstrated the operability of that method for heating tissue, two adverse concomitant effects precluded its acceptance as a useful modality for treating carcinomata. First, iron oxide in substantial concentrations tends to be toxic to and/or rejected by the body. Second, and more importantly, the normal tissue surrounding the tumor became too hot during exposure to the magnetic field and was subject to necrosis. This second effect was due to dielectric or eddy-current heating, i.e., heating resulting from ionic conductivity of body tissue and fluids.
It had been recognized that more disparate heating between the suscepted region and the surrounding tissue could be achieved if the excitation field was of lower frequency. Thus, the heating of normal tissue via dielectric or eddy-current heating, (a function of the square of the product of field and frequency) would be minimized, whereas magnetic hysteresis heating, which varies linearly with field frequency, would be maximized.
The patentees disclosed materials or compositions which exhibited magnetic properties which maximize hysteresis loss, i.e., they exhibited high magnetization, good coercivity, and high loop squareness, each of those properties contributing to hysteresis heating. That combination of properties permitted the use of RF frequencies of sufficiently low levels that essentially only magnetic hysteresis heating of the suscepting material could occur; dielectric or eddy-current heating effects being reduced to a negligible level.
The preferred embodiments of the invention contemplated encapsulating magnetic iron-containing crystals consisting essentially of magnetite or a ferrite in a glass, glass-ceramic, or sintered ceramic matrix, the crystals having a diameter exceeding superparamagnetic size.
It is explained in that patent that temperatures within the range of about 41.degree.-44.degree. C. will cause necrosis of tumor tissue, whereas normal animal tissue is not destroyed until temperatures in the vicinity of about 48.degree. C. are reached. It was observed, however, that brief exposures to temperatures up to 50.degree. C. could be tolerated with very little necrosis of normal tissue. Such higher temperatures destroy tumor cells very quickly, thereby significantly reducing the time required for treatment. Accordingly, a series of pulses of RF magnetic energy can be utilized, the time of each pulse required to produce necrosis of tumor tissue, while having substantially no effect upon normal tissue, being readily determined empirically. Likewise, the concentration of mediating material having magnetic iron-containing crystals incorporated therein necessary to cause the desired hysteresis heating effect can also be readily determined empirically. Hence, the upper temperature of heating can be controllably regulated by suitably selecting the suscepting material and restricting the quantity thereof administered.
Localized hyperthermia can be accomplished in several ways. For example, an aqueous dispersion of the target material in very finely-divided form can be injected directly into a tumor and/or into normal tissue contiguous with the tumor. Subsequent exposure to the RF-induced magnetic field causes the target material to be heated.
In another method, an aqueous dispersion of the powdered suscepting target material is injected via intravenous or arterial routes at a site near or distal to the tumor. The flow of blood provides the transport to the site of the tumor. Assistance in moving the injected material may be engendered by guiding the passage with a magnet.
Where there is surgical exposure of a tumor, the target material can be injected into or applied onto the outside of the tumor. Hyperthermia will be induced through magnetic field induction heating prior to and/or after the incision has been closed. Hence, the treatment can comprise a series of exposures. The target material will desirably be inert or else harmlessly degraded by body fluids, the degradation taking place so slowly that the target material will remain at the site of the tumor for a significant length of time. This circumstance enables a succession of individual treatments with RF fields to be conducted to secure localized heating with only one implacement of mediating material.
Further, it is possible to derivatize the target particles with tumor specific ions or with antibodies and/or other similarly bioactive molecules directed against a tumor. This permits specific localization of the target material in and/or around the tumor. Stated differently, agents specific to a particular tumor can be attached directly to the target material or by the use of chelating or other coupling agents.
It is also possible to utilize the physical properties of tumors in localizing the target material in the areas thereof. As an illustration, tumors commonly exhibit pH values either in the range of about 3-4 or in excess of about 8.5. The pH of body fluids is about 7.4. Consequently, it is possible to design magnetic target materials which precipitate at the pH value manifested by a particular tumor. Thereupon, the precipitated material can be heated with the RF magnetic field.
Finally, in yet another method, the target material can be presensitized to have an affinity for a tumor species and thereafter can be delivered to the tumor site by injection, cannulation, magnetic guidance, and the like. Such presensitization may involve the surface of the target material or the bulk thereof. To illustrate, the target material can be etched and the pores filled with a sensitizing agent. Examples of such sensitizing agents include K/Mg for low pH tumors and gallium for lung carcinomata.
In summary, the basic consideration in the above patent was given to a RF range of frequencies and a field strength of a magnetic field to minimize eddy-current heating of normal tissue while hysteresis heating, due to the biocompatible, non-toxic suscepting target material, was taking place. Because of the dependence of the eddy-current heating on field and frequency [approximately (wH).sup.2 ], the working frequency was determined to be in the 10 kilohertz region or below with the field strength in the vicinity of 700 oersteds. The suscepting magnetic target material was required to develop sufficient power (watts/cm.sup.3 of tissue) under the above field and frequency conditions to produce temperatures in the 41.degree.-44.degree. C. range, while not causing toxic or rejection problems within the body. Specific reference is made to that patent for further information regarding the treatment of tumors by hyperthermia.
Published U.K. Application GB No. 2,024,007A discloses a method for employing hyperthermia to kill cancer cells which contemplates two general steps:
First, minute particles of a ferromagnetic, diamagnetic, or paramagnetic material compatible with living tissue are introduced into the cancer cells, the sole ferromagnetic material mentioned being ferric hydroxide; and
Second, the cancer cells and adjacent normal cells are subjected to a high frequency electromagnetic field, the field having a range of frequencies from 50 kilohertz to 10 megahertz and magnetic field strength of 400-800 oersteds, preferably 550-650 oersteds.
At least two fundamental aspects of that disclosure serve to differentiate it from that of U.S. Pat. No. 4,323,056, supra:
(1) U.S. Pat. No. 4,323,056 employs a RF magnetic field which has a frequency sufficiently low that essentially only magnetic hysteresis heating of the suscepting material can occur; and PA0 (2) U.S. Pat. No. 4,323,056 demands that the suscepting material be biocompatible, both chemically and physically, with normal animal tissue. PA0 (a) intracellularly injecting particles having a size less than 1 micron demonstrating ferromagnetic, paramagnetic or diamagnetic properties into the cells; PA0 (b) determining the magnetic susceptibility of the intracellular particles; and then PA0 (c) correlating the measured magnetic susceptibility to corresponding temperature of the particles. PA0 (a) forming microcapsules comprising the therapeutic agent in combination with a magnetically responsive substance; PA0 (c) directing the microcapsules to a desired site via the application of a magnetic field.
In contrast, the published application teaches the utilization of dielectric or eddy-current heating of the suscepting material in combination with hysteresis heating. As observed in U.S. Pat. No. 4,323,056 dielectric heating resulting from ionic conductivity of body tissue and fluids causes normal tissue adjacent to a tumor to become too hot, thereby leading to necrosis thereof. Furthermore, ferric hydroxide is known to be toxic to animal tissue.
In a literature article, "Potential Treatment of Cancer by Electromagnetic Heating", Surgery, Gynecology and Obstetrics, April, 1960, pages 499-500, R. K. Gilchrist refers to a report by one Medal (no citation of the report is provided) indicating that it is possible to cause local necrosis in tissue containing 0.005 gram of magnetic particles having diameters of 0.02-0.1 micron through exposure to a field of 1,500,000 volt-amperes, 450 oersteds, and 1.1 kilohertz. That exposure effects heating via hysteresis. The article, however, is principally concerned with eddy-current heating and inductothermy. There is no statement of any advantage to be gained in utilizing hysteresis heating instead of eddy-current heating and the publication concludes with the prediction that eventually hyperthermia will evolve to such an extent that target materials will not be necessary. Moreover, there is no statement as to the identity of any operable magnetic material. Yet, as pointed out in U.S. Pat. No. 4,323,056, iron oxide, the magnetic material most used in the prior hyperthermia work, is toxic to animal tissue. Consequently, where such is to be employed as the target material, U.S. Pat. No. 4,323,056 teaches enveloping it in a glass, glass-ceramic, or ceramic matrix.
U.S. Pat. No. 4,136,683 describes a three-step process for measuring the intracellular temperature of cells within an animal body:
The patent has no disclosure regarding hyperthermia, i.e., the reduction of a cancerous mass via localized heating of cancerous cells. On the contrary, the patent simply seeks to measure the internal temperature of cells. Moreover, the patent indicates the effectiveness of any ferromagnetic, paramagnetic, or diamagnetic material. In contrast, the present invention requires the use of magnetic materials exhibiting very explicitly defined characteristics. Furthermore, the patent describes the use of a high frequency electromagnetic field, whereas the instant invention utilizes fields of relatively low frequencies. Finally, the patent makes no mention of encapsulating the magnetic particles within a material non-toxic to animal tissue.
U.S. Pat. No. 2,161,292 is concerned with a device for providing a more efficient means for transmitting electromagnetic radiations to an animal or human body to thereby subject the body to the influence of transmitted energy. The device consists of a dipole encapsulated within a ceramic member and is connected via wires to an oscillator generator, the ceramic member having a dielectric constant similar to that of the body to be treated. The shape of the ceramic member is so designed that the energy is transmitted therethrough to the body without passing through air. The patent indicates that air causes reflection phenomena which severely limit the amount of transmitted energy received by a body.
The patent does not disclose implanting a magnetic susceptor in an animal body. Furthermore, the patent does not teach the necessity for utilizing a susceptor material having iron-containing particles therein to impart a desired coercive force to the material. Finally, the patent makes no reference to a RF magnetic field or to hysteresis heating, both of those features constituting the heart of the instant invention.
U.S. Pat. No. 3,474,777 describes means for localizing a therapeutic agent at a particular treatment site within a body. That means contemplated three basic steps:
(b) injecting the microcapsules into the body, e.g., into the blood stream; and then
No reference whatever is made to hyperthermia. No mention is made of a RF magnetic field. There is no discussion of hysteresis heating.
None of the above three patents alone or any combination thereof can be deemed to teach the use of a mediating material having ferromagnetic particles incorporated therewithin which is non-toxic to animal tissue, coupled with the limitation that heating will be essentially confined to hysteresis heating.